US2025372225A1PendingUtilityA1
A quantitative pharmacological model of enzyme replacement therapy
Est. expiryJun 13, 2042(~15.9 yrs left)· nominal 20-yr term from priority
G16H 20/10G16B 5/00A61P 35/00G16H 50/50
59
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Claims
Abstract
This disclosure relates to systems and methods for modeling the pharmacokinetics and pharmacodynamics of enzyme replacement therapies (ERT) in various systems and tissues.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A method of generating a pharmacokinetic and/or pharmacodynamic profile of a therapeutic agent in a subject, the method comprising using of a model in which a plurality of variables represent a plurality of input rates and output rates for one or more compartments,
wherein the therapeutic agent comprises a TfR-binding moiety, wherein the input rate and the output rate of the therapeutic agent depend on the binding affinity of the TfR-binding moiety to TfR and the valency of the TfR-binding moiety.
2 . A method of determining the efficacy of a therapeutic agent in a subject, the method comprising:
a) determining a pharmacokinetic and pharmacodynamic profile in the subject, using a model in which a plurality of variables represent a plurality of input rates and output rates for one or more compartments; b) providing the concentration of the therapeutic agent in a sample collected from the subject; and c) estimating, based on the concentration of the therapeutic agent in the sample and the pharmacokinetic profile and the pharmacodynamic profile in the subject, the concentration of the therapeutic agent in a tissue.
3 . The method of claim 2 , wherein the therapeutic agent comprises a TfR-binding moiety.
4 . The method of claim 3 , wherein the input rate and the output rate of the therapeutic agent depend on the binding affinity of the TfR-binding moiety to TfR and the valency of the TfR-binding moiety.
5 . The method of any one of claims 1-4 , wherein the one or more compartments comprise a superficial brain compartment, a deep brain compartment, a cerebrospinal fluid (CSF) compartment, wherein the superficial brain compartment and the cerebrospinal fluid compartment are connected.
6 . The method of claim 5 , wherein the one or more compartments further comprise a CNS endothelial space compartment and a circulation compartment, wherein the deep brain compartment and the CNS endothelial space compartment are connected.
7 . The method of claim 6 , wherein the CNS endothelial space compartment represents a blood-brain barrier.
8 . The method of any one of claims 2-7 , wherein the tissue is plasma, cerebrospinal fluid, or brain.
9 . The method of any one of claims 1-8 , wherein the therapeutic agent comprises an enzyme.
10 . The method of claim 9 , wherein the enzyme is a lysosomal enzyme.
11 . The method of claim 9 , wherein the enzyme is iduronate-2-sulfatase.
12 . The method of any one of claims 9-11 , wherein the method further comprises estimating the concentration of an enzyme substrate and/or an enzyme product in the tissue.
13 . The method of any one of claims 2-12 , wherein the concentration of the therapeutic agent in the superficial brain compartment is determined by transport of the therapeutic agent from CSF and/or transport of the therapeutic agent across brain endothelium.
14 . The method of claim 13 , wherein the concentration of the therapeutic agent in the superficial brain compartment is calculated by
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15 . The method of any one of claims 2-14 , wherein the concentration of the therapeutic agent in the deep brain compartment is determined by transport of the therapeutic agent across brain endothelium.
16 . The method of claim 15 , wherein the concentration of the therapeutic agent in the deep brain compartment is calculated by
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17 . The method of any one of claims 2-16 , wherein the concentration of the therapeutic agent in the CSF compartment is determined by transport of the therapeutic agent across blood:CSF barrier and/or exchange of the therapeutic agent with the superficial brain compartment.
18 . The method of claim 17 , wherein the concentration of the therapeutic agent in the CSF compartment is calculated by
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19 . A method of estimating the concentration of a therapeutic agent in a subject, the method comprising:
a) determining a pharmacokinetic and pharmacodynamic profile in the subject, using a model in which a plurality of variables represent a plurality of input rates and output rates for one or more compartments: b) measuring the concentration of the therapeutic agent in a sample collected from the subject; and c) estimating, based on the concentration of the therapeutic agent in the sample and the pharmacokinetic profile and the pharmacodynamic profile in the subject, the concentration of the therapeutic agent in a tissue.
20 . The method of claim 19 , wherein the one or more compartments comprise a superficial brain compartment, a deep brain compartment, a cerebrospinal fluid (CSF) compartment, wherein the superficial brain compartment and the cerebrospinal fluid compartment are connected.
21 . The method of claim 19 or 20 , wherein the one or more compartments further comprise a CNS endothelial space compartment and a circulation compartment, wherein the deep brain compartment and the CNS endothelial space compartment are connected, and the deep brain compartment and the superficial brain compartment are not connected.
22 . The method of claim 21 , wherein the CNS endothelial space compartment represents a blood-brain barrier.
23 . The method of any one of claims 19-22 , wherein the therapeutic agent comprises a TfR- binding moiety.
24 . The method of claim 23 , wherein the input rate and the output rate of the therapeutic agent depend on the binding affinity of the TfR-binding moiety to TfR and the valency of the TfR-binding moiety.
25 . A method of determining the dosage of a therapeutic agent in a subject, the method comprising:
a) determining a pharmacokinetic and pharmacodynamic profile in the subject, using a model in which a plurality of variables represent a plurality of input rates and output rates for one or more compartments; b) measuring the concentration of the therapeutic agent in a sample collected from the subject; and c) estimating, based on the concentration of the therapeutic agent in the sample and the pharmacokinetic profile and the pharmacodynamic profile in the subject, the dosage of the therapeutic agent in the subject.
26 . The method of claim 25 , wherein the one or more compartments comprise a superficial brain compartment, a deep brain compartment, a cerebrospinal fluid (CSF) compartment, wherein the superficial brain compartment and the cerebrospinal fluid compartment are connected.
27 . The method of claims 26 , wherein the one or more compartments further comprise a CNS endothelial space compartment and a circulation compartment, wherein the deep brain compartment and the CNS endothelial space compartment are connected, and the deep brain compartment and the superficial brain compartment are not connected.
28 . The method of claim 27 , wherein the CNS endothelial space compartment represents a blood-brain barrier.
29 . The method of any one of claims 25-28 , wherein the therapeutic agent comprises a TfR- binding moiety.
30 . The method of claim 29 , wherein the input rate and the output rate of the therapeutic agent depend on the binding affinity of the TfR-binding moiety to TfR and the valency of the TfR-binding moiety.
31 . A method of estimating the concentration of an enzyme substrate or an enzyme product in a subject, the method comprising:
a) determining a pharmacokinetic and pharmacodynamic profile in the subject, using a model in which a plurality of variables represent a plurality of input rates and output rates for one or more compartments; b) measuring the concentration of the enzyme substrate or enzyme product in a sample collected from the subject; and c) estimating, based on the concentration of the enzyme substrate or enzyme product in the sample and the pharmacokinetic profile and the pharmacodynamic profile in the subject, the concentration of the enzyme substrate or enzyme product in a tissue.
32 . The method of claim 31 , wherein the one or more compartments comprise a superficial brain compartment, a deep brain compartment, a cerebrospinal fluid (CSF) compartment, wherein the superficial brain compartment and the cerebrospinal fluid compartment are connected.
33 . The method of claim 32 , wherein the one or more compartments further comprise a CNS endothelial space compartment and a circulation compartment, wherein the deep brain compartment and the CNS endothelial space compartment are connected, and the deep brain compartment and the superficial brain compartment are not connected.
34 . The method of claim 33 , wherein the CNS endothelial space compartment represents a blood-brain barrier.
35 . The method of any one of claims 31-34 , wherein the substrate or enzyme product is a glucosaminoglycan (GAG).
36 . The method of claim 35 , wherein the glucosaminoglycan is heparan sulfate or dermatan sulfate.
37 . The method of claim 35 or 36 , wherein the concentration of the substrate or enzyme product depends on the binding affinity of the TfR-binding moiety to TfR and the valency of the TfR-binding moiety.
38 . A system for performing the method of any one of claims 1-37 .
39 . A method for determining response to an enzyme replacement therapy in a subject, comprising:
a. modeling a pharmacokinetic profile and a pharmacodynamic profile in the subject using a state variable model in which a plurality of state variables represent a plurality of inputs and outputs of the model; b. determining the pharmacokinetic profile for the subject based on the state variables of the model; and c. determining the pharmacodynamic response in the subject based upon the determined pharmacokinetic profile, wherein the pharmacodynamic response is indicative of response to the enzyme replacement therapy.
40 . The method of claim 39 , wherein the pharmacodynamic response is a reduction in a glucosaminoglycan (GAG) substrate level relative to a baseline level measured prior to administration of the enzyme replacement therapy.
41 . The method of claim 39 or 40 , wherein the pharmacokinetic profile and/or the pharmacodynamic response are determined in the brain.
42 . The method of any one of claims 39-41 , wherein the pharmacokinetic profile and/or the pharmacodynamic response are determined in the cerebrospinal fluid (CSF).
43 . The method of any one of claims 39-42 , wherein the model incorporates a parameter based on the ratio of superficial brain:deep brain biodistribution of the enzyme.
44 . The method of any one of claims 39-43 , wherein the model incorporates a parameter based on the biodistribution of the enzyme in the vascular compartment of the blood-brain barrier.
45 . The method of any one of claims 39-44 , wherein the model incorporates a parameter based on the biodistribution of the enzyme in the parenchymal compartment of the blood-brain barrier.
46 . The method of any one of claims 39-45 , wherein the plurality of state variables include one or more of:
a. route of administration of the ERT; b. dose amount of the ERT; c. mannose-6-phosphate receptor (M 6 PR) binding affinity; and d. penetration depth of the ERT from CSF.
47 . The method of any one of claims 39-46 , wherein the plurality of state variables include TfR-binding affinity of the ERT and/or valency of TfR binding of the ERT.
48 . The method of any one of claims 39-47 , wherein the enzyme target for ERT is a lysosomal storage disease enzyme.
49 . The method of claim 48 , wherein the lysosomal storage disease enzyme is selected from the group consisting of: IDS, SGSH, IDUA, GAA, ARSA, NAGLU, and GCase.
50 . A method of determining a therapeutically effective dose for an ERT, comprising:
a. modeling a pharmacokinetic profile and a pharmacodynamic profile in the subject using a state variable model in which a plurality of state variables in a state vector represent a plurality of inputs and outputs of the model; b. determining the pharmacokinetic profile for the subject based on the state variables of the model; and c. determining the pharmacodynamic response in the subject based upon the determined pharmacokinetic profile; wherein a change in the pharmacodynamic response in the subject relative to a baseline level is indicative of therapeutic efficacy of the dose.Join the waitlist — get patent alerts
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